Cyclodextrins are cyclic multicyclopyranose units connected by .alpha.-(1,4) linkages. The most widely known cyclodextrins are .alpha., .beta. and .gamma.-cyclodextrins. Derivatives of these cyclodextrins with improved properties are also known and used in the pharmaceutical field. The cyclic nature of the cyclodextrins, the hydrophobic properties of their cavities as well as the hydrophilic character of their outer surfaces, enables them to interact with other chemicals and to produce inclusion compounds which are characterized by improved solubilities and stabilities. Fields of potential applications of cyclodextrins include pharmaceuticals, fine chemicals, industrial chemicals and biological active substances.
Numerous reviews and patents related to the use of cyclodextrins and their derivatives to prepare inclusion complexes of drugs are found in the literature, for example, D. Duchene, Cyclodextrins and their Industrial uses, Editions de Sante, Paris, 1987, Chapter 6 (211-257), Chapter 8 (297-350), Chapter 10 (393-439); D. Duchene et al, Acta Pharma Technol. 36(1)6, 1-6, 1990; D. Duchene et al, Drug Dev. Ind. Pharm., 16(17), 2487-2499, 1990; C. Hunter et al, European Patent Publication No. EP 0346006, December 1988.
Inclusion complexes prepared to specifically improve water solubility and hence bioavailability of poorly soluble drugs have been reported by workers such as D. D. Chow et al, Int. J. Pharm., 28, 95-101, 1986; F. A. Menard et al, Drug Dev. Ind. Pharm., 14(11), 1529-1547, 1988; F. J. Otera-Espinar et al, Int. J. Pharm., 75, 37-44, 1991; and Berand M. Markarian et al, European Patent Publication No. EP 0274444, July 1988. Chemical modifications of cyclodextrins to prepare derivatives that further improve solubility of water insoluble drugs have been described, for example, by J. Pitha, U.S. Pat. No. 4,727,064, February 1988; N. S. Bodor, U.S. Pat. No. 5,024,998, July 1991.
In connection with the use of acids or buffers with cyclodextrins, the effects of the latter on dissociation constants of acidic organic compounds, including non-carboxylic acids, have been reported by K. Connors et al, J. Pharm. Sci., 65 (3), 379-383, 1976, but these workers have not addressed the issue of solubility. As an extension to this work, equilibrium constants of some prostaglandins in the presence of .alpha.- and .beta.-cyclodextrins have been determined in phosphate buffer solutions, as reported by K. Uekama et al, Chem. Pharm. Bull., 26 (4), 1195-1200, 1978. Furthermore, .beta.-cyclodextrin inclusion complexes of several non-steroidal anti-inflammatory drugs have been correlated for their dissolution behavior at different pH values by V. Zecchi et al, Proc. Eur. Congr. Biopharm. Pharmacokinet. 3rd, (1), 526-531, 1987; V. Zecchi et al, Pharma Acta Helv., 63 (11), 299-302, 1988; Zecchi et al concluded that the dissolution rate of such complexes is scarcely altered by changing the pH. Also, the diffusion of free and .beta.-cyclodextrin-complexed non-steroidal anti-inflammatory drugs have been determined at different pH values by I. Orienti et al, Arch Pharm.(Weinheim, Germany) 322(4), 207-211, 1989. A naproxen/.beta.-cyclodextrin complex has been examined for solubility in buffered aqueous media by F. J. Otero-Espinar et al, lnt. J. Pharm., 79, 149-157, 1992; N. (Celebi et al, Int. J. Pharm., 78, 183-187, 1992; N. Erden, Int. J. Pharm., 48, 83-89, 1988. Dissolution of famotidine, and the .beta.-cyclodextrin inclusion compound of the drug have been reported at pH 7.4 by M. Hassan et al, Int. J. Pharm., 58, 19-24, 1990. The effects of pH on the complexation of hydroclorothiazide, ibuprofen and diazepam with .beta.-cyclodextrin cyclodextrin have been discussed by F. Menard et al, Drug Dev. Ind. Pharm., 16(1), 91-113, 1990; these workers have found in their experiments that the relationship between solubility and concentration is the same at different pH levels. The dissolution of tolbutamide/.beta.-cyclodextrin complex has been compared to that of the drug itself and solid dispersions at pH 2 by F. Kedzierewicz et al, Int. J. Pharm., 58, 221-227, 1990.
Pharmaceutical formulations containing cyclodextrins typically contain other ingredients commonly used in pharmaceuticals, for example, pH adjusters (acids, bases, buffers), effervescing agents and the like, to create forms suitable for administration. For example, International Publication No. WO85/02767, July 1985, has disclosed preparing pharmaceutical compositions by dissolving a selected cyclodextrin derivative in water and adding the desired drug to form an inclusion compound, wherein the water "may further comprise physiologically compatible compounds such as sodium chloride, potassium nitrate, glycose, mannitole, sorbitol, xylitol or buffers such as phosphate, acetate or citrate buffer." Hirai et al, U.S. Pat. No. 4,659,696, April 1987, have described various non-oral, non-injectable pharmaceutical compositions containing a drug which is poorly absorbable through the gastrointestinal tract and cyclodextrin, which may contain a variety of excipients and pH adjusters, such as an acid, a base or a buffer solution. As examples of the acid, there are mentioned "inorganic acids (e.g., hydrochloric acid, boric acid, phosphoric acid, carbonic acid, bicarbonic acid, etc.), amino acids and organic acids (e.g., monocarboxylic acids, oxycarboxylic acids, polycarboxylic acids)." Also, Chiesi et al, in U.S. Pat. No. 4,603,123, July 1986, in describing pharmaceutical compositions containing piroxicam/cyclodextrin complexes, show an effervescent tablet formulation comprising citric acid and glycine sodium carbonate in equal amounts, but these are indeed typical effervescing agents and, moreover, are added after the drug/cyclodextrin complex has already been formed. Similarly, in C. Hunter, European Patent Publication No. 0346006 relating to pharmaceutical compositions comprising ibuprofen-cyclodextrin complexes, there are examples of non-effervescent, effervescent and slightly effervescent formulations comprising trisodium citrate, citric acid and sodium bicarbonate, but these ingredients are added to the already formed ibuprofen complexes. None of these earlier workers has attached any significance to particular acids, or has recognized that selected acids could be used to improve the solubilization and/or complexation with cyclodextrins of drugs which are insoluble or sparingly soluble in water. And, of course, no such improvement would be present, for example, in the case of Chiesi et al's effervescent tablets, since the citric acid component is only present in sufficient amount to effervesce together with the glycine sodium carbonate; there is no additional citric acid present to serve as a solubilizer, as provided by the present invention as described in detail hereinbelow.
Despite the advances in the pharmaceutical arts made possible by the use of cyclodextrins with drugs which are insoluble or only sparingly soluble in water, there remains a need for further improvements in drug/cyclodextrin formulations. .beta.-Cyclodextrin, although considerably less expensive than its derivatives, increases drug solubility much more modestly than the derivatives and, in some instances, does not confer sufficient solubility at a low enough concentration to provide a feasible product, for example, a small enough tablet to be readily swallowed. Thus, there is a real need in this art for a means of significantly increasing the solubility of drugs in the less efficient cyclodextrins. On the other hand, the derivatized cyclodextrins tend to be very expensive; thus, there is also a real need for enhancing the solubility of drugs with such expensive cyclodextrins so that considerably smaller amounts of the cyclodextrins are required to achieve an effect comparable to that which could previously be obtained.